Meperidine is a synthetic opioid analog that is frequently used for acute pain management. It is derived from phenylpiperidine and is active at both the mu- and kappa-opioid receptors. Meperidine is also commonly known as pethidine or by its brand name Demerol. Compared to morphine, it has a shorter duration but faster onset of action and is around 7-10 times less potent (Latta et al., 2002). It is administered in the form of meperidine hydrochloride, which is supplied for oral administration as either tablets (50 or 100 mg) or as syrup (10 mg/ml). A solution of the drug (25-100 mg/ml) is also available for parenteral injection and can be given epidurally, intraperitoneally, or intrathecally (Baselt, 2008).
Meperidine hydrochloride is readily absorbed from the gastrointestinal tract and is rapidly and extensively distributed throughout the tissues (Moffat et al., 2003). The most clinically significant metabolic pathway is through N-demethylation to form normeperidine, the only active metabolite (Latta et al., 2002). FIG. 1 shows the structure of meperidine and normeperidine. Meperidine undergoes first-pass metabolism, meaning that only around 50% reaches systematic circulation. About 7% of meperidine will be excreted unchanged in urine and around 17% will be eliminated in the form of normeperidine (Baselt, 2008). Approximately 70% of the administered dose will be excreted in urine within 24 hours (Moffat et al., 2003). Absorption of the drug varies when administered as an intramuscular injection, with peak plasma concentrations occurring 1-2 hours after administration. The plasma elimination half-lives of meperidine and normeperidine are 3-4 hours and 15-20 hours, respectively (Demerol Prescribing Information datasheet, Sanofi-Aventis). Normeperidine is only half as effective an analgesic as its parent compound. However, it has up to 3 times the neurotoxic potential, having significant adverse effects on the central nervous system (CNS). It is also more active as a convulsant and has an extended half-life (14-48 hours, as opposed to 3-6 hours for meperidine) (Latta et al., 2002). It is excreted renally and thus the half life is prolonged in patients with renal dysfunction. Normeperidine is rarely detected in plasma following a single administration (Baselt, 2008). However, it can accumulate in plasma following chronic administration, particularly following renal failure (Moffat et al., 2003) and may be detected at concentrations greater than the parent drug (Baselt, 2008). The ratio of normeperidine to meperidine has been suggested as an important indicator of possible CNS excitation side effects, with a ratio greater than one representing a higher risk (Kaiko et al., 1983). Both meperidine and normeperidine have been detected in cerebrospinal fluid (Sweetman, 2011). Meperidine/normeperidine side effects can be manifested as a wide range of symptoms with varying degrees of severity including irritability, agitation, tremors, tachycardia, muscle twitches, hypertension, disorientation, and grand mal seizures. A daily dose of meperidine as low as 260 mg has been reported to cause grand mal seizures, while doses as low as 46 mg per day have been reported as causing muscle twitches or tremors (Latta et al., 2002). Meperidine has also been linked with increased risk of delirium in elderly patients (Marcantonio et al., 1994) and possesses complex pharmacodynamics not in common with other first-line opioids, including inhibition of the re-uptake of the neurotransmitter serotonin, which can lead to the potentially fatal serotonin syndrome (Latta et al., 2002). In addition, these side-effects are not reversible with traditional opioid antagonists such as naxolone, which by antagonizing the depressant effects may even enhance the convulsant activity of meperidine/normeperidine (Umans & Inturrisi, 1982).
The ease of availability and short duration of action has made meperidine a favourite drug of abuse amongst medical professionals (Murphree, 1962; Wallot & Lambert 1982). Although iatrogenic addiction following long-term medication of narcotic analgesics has been noticed, it has rarely been documented (Jiang, 1992). Addiction to meperidine has similar characteristics to heroin addiction, and physical withdrawal can be managed using methadone or clonidine (Jiang, 1992). There have also been reports of the alteration and modification of controlled substances, including meperidine, to produce “designer drugs” that have previously been able to temporarily elude controlled substance regulations (Jerrard, 1990). Both meperidine and its active metabolite normeperidine are target analytes on the society of forensic toxicologists (SOFT) list for the detection limits of common drugs used in drug facilitated sexual assault (DFSA). In the United States, meperidine including its isomers, esters, salts, and salts of isomers, has been placed on schedule II of the Controlled Substances Act (DEA) and in the UK (as pethidine) under class A.
Due to concerns surrounding its toxic side-effects, many health care organisations are either restricting its use or phasing it out altogether, replacing it with less toxic opioid analgesics. However, meperidine may still be beneficial for short-term pain management, treatment of post-operative shivering, and the prevention and treatment of drug-induced or blood product-induced rigors (Koczmara et al., 2005). When it is still administered, it would be important to accurately monitor build-up of the parent and especially the active metabolite in patients. Currently available antibodies/immunoassays for meperidine have low cross reactivity with normeperidine and thus, if used for therapeutic drug monitoring (TDM) purposes, may grossly underestimate levels of this toxic metabolite (Table 1). A liquid chromatography based study found a 98.7% increase in detection of positive specimens when both meperidine and normeperidine were measured compared to meperidine on its own (DePriest et al., 2010). The unique properties, including the high sensitivity of the monoclonal antibody described herein, which detects both the parent drug and its metabolite in approximately a one to one ratio, would be beneficial for use in immunoassays, for TDM purposes, and in extending the window of detection for cases of abuse and DFSA.
TABLE 1Specificity of a selection of availablemeperidine antibodies/immunoassays*NormeperidineMeperidinespecificitySensitivity(Relative toSupplierProduct(IC50)meperidine 100%)NeogenMeperidineNot disclosed2.3%ready-to-use kitImmunalysisdirect ELISA kit≈40 ng/ml7.0%InternationalPolyclonal AbNot disclosed12.7%DiagnosticSystems*data taken from manufacturers instructions for use